RAC1b overexpression confers resistance to chemotherapy treatment in colorectal cancer

Resistance to chemotherapy represents a major limitation in the treatment of colorectal cancer. Novel strategies to circumvent resistance are critical to prolonging patient survival. Rac1b, a constitutively activated isoform of the small GTPase Rac1, is upregulated with disease progression and promotes cell proliferation and inhibits apoptosis by activation of NFκΒ signaling. Here, we show that Rac1b overexpression correlates with cancer stage and confirmed Rac1b expression is associated with increased growth through enhancing NFκB activity. Rac1b knockdown reduced cellular proliferation and reduced NFκB activity. Surprisingly, Rac1b expression and NFκB activity were upregulated in cells treated with chemotherapeutics, suggesting that Rac1b facilitates chemo-resistance through activation of NFκB signaling. Knockdown of Rac1b or Rac inhibtion increases the sensitivity of the cells to oxaliplatin. When used in combination, inhibition of Rac prevents the increase in NFκB activity associated with chemotherapy treatment and increases the sensitivity of the cells to oxaliplatin. While Rac inhibition or oxaliplatin treatment alone reduces the growth of colorectal cancer in vivo, combination therapy results in improved outcomes compared to single agents alone. We provide the first evidence that Rac1b expression confers resistance to chemotherapy in colorectal cancer. Additionally, we show that the use of a Rac inhibitor prevents chemoresistance by blocking activation of chemotherapy induced NFκB signaling providing a novel strategy to overcome resistance to chemotherapy in colorectal cancer.